Potential Therapeutic Targets for TNBC Therapy: Comparison
View Latest Version
Please note this is a comparison between Version 2 by Nora Tang and Version 1 by AISWARYA CHAUDHURI.
TNBC exhibits high heterogeneity, which is the major limitation of chemotherapy. Also, TNBC is regarded as an aggressive type of cancer that grows faster and metastasizes to the brain and visceral organs, providing a much shorter average survival time of about 12 months to patients suffering from advanced TNBC. Therefore, the recognition of definitive targets, for providing efficient treatment against TNBC, becomes a noteworthy task.
  • chemotherapy
  • nanoparticles
  • targeted therapy
  • triple-negative breast cancer (TNBC)

1. Notch Signaling Pathways

The Notch signaling pathway is considered an exceptionally preserved targeted pathway that involves juxtracrine (cell-to-cell) communication, thus regulating several critical cellular processes [[1]]. Notch signaling is known for regulating self-renewal as well as differentiation processes, required for normal development of the mammary gland [[2],[3]]. It was observed that the signaling pathway is triggered when the Notch ligand interacts with the Notch receptor, situated on the adjoining cell. Up till now, four Notch receptors and five Notch ligands have been identified. The five Notch ligands identified are Delta-like (DII)-1, 3, and 4, and Jagged (JAG)-1, and 2. Structurally, it was observed that all the Notch ligands are transmembrane proteins, having an extracellular DSL domain and multiple EGF-like repeats. The extracellular DSL domain is responsible for mediating the binding process between the Notch receptor and Notch ligands. In addition to this, the JAG ligand consists of an extra domain enriched with cysteine, which is absent in the DII ligand [[4]]. It was observed that a Notch ligand-receptor complex was formed when the Notch ligand binds with the Notch receptor. The binding procedure is facilitated by two proteolytic enzymes, i.e., ADAM (disintegrin metalloprotease) and TACE (TNF-α converting enzymes), which further aids in releasing the ectodomain of the Notch receptor [[5],[6]]. The proteolytic activity then converts the Notch ligand-receptor complex into NEXT (Notch extracellular truncation). Finally, the NEXT is broken down via γ-secretase, and the Notch intracellular domain (NICD) get discharged, which then translocates from the cytoplasm to the nucleus [[7]], where it binds with the transcriptional activator, namely CSL complex (CBF1, RBPJK/Su(H)/LAG1, and Mastermind (MAML1-3, and MED3)) [[8],[9]]. The binding then orchestrates CSL-complex activation, leading to transcription of downstream targets, which includes genes like ER, Hes, Hey, and VEGFR3 (vascular endothelial growth factor receptor 3), transcriptional factors like NF-κB2 and c-Myc, cell cycle regulators (cyclin D1 and p21), growth factor receptors, and angiogenesis and apoptosis modulators [[1],[10]]. It was observed that dysregulation of the Notch signaling pathway often leads to aberrant self-renewal and differentiation of stem cells, which results in carcinogenesis [[11],[12]].
In a study by Speiser et al., 2012, it was found that the progression of TNBC was associated with increased expression of Notch 1 and Notch 4 receptors [[13]]. The abnormal activation of NOTCH receptors results in aberrant controlling of the transcription of several oncogenes as well as tumor suppressor genes [[14]], which include CYCLIN D1, c-MYC, PTEN, and the BCL-2 pro-survival proteins [[15],[16],[17]]. Loss or reduced expression of NICD, NUMB (a negative regulator of EMT) also leads to TNBCs in association with poor clinical outcomes [[18],[19]]. In 1987, Gallahan et al. inserted a mutagenic mouse mammary tumor virus (MMTV), which then generated truncated and active Notch1 and 4 receptors, resulting in the formation of breast cancer in mice [20]. On a similar trait, in 2013, Reipas and his associates revealed that p90 ribosomal S6 kinase, an oncogenic transcription factor is required for the growth of TNBC, which was found to be an activator of the Notch4 signaling pathway [[21]]. Thus, there exists strong evidence that indicates the involvement of the NOTCH signaling pathway, especially NOTCH1/NOTCH4 into the etiology of TNBC. Hence, targeting the Notch signaling pathway should provide a promising treatment platform against TNBC.

2. Hedgehog (Hh) Signaling Pathway

Hh signaling is also considered a preserved pathway, just like notch pathways. Hh signaling acts as a key signaling cascade in the proper development of the embryonic mammary gland as well as ductal morphogenesis. Hh signaling is also known to take part in EMT [[22]]. Hh signaling pathway is comprised of three ligands, namely Sonic Hedgehog (Shh), Desert Hedgehog (DHh), and Indian Hedgehog (IHh), where Sonic Hedgehog was regarded as the most targeted, one transmembrane receptor, PTCH, and one co-receptor, SMO. It was observed that the co-receptor SMO is required for the functioning of the Hh signaling pathway, but it has been inhibited by PTCH. So, the binding of the Hh ligand with the PTCH receptor led to its inactivation, which indirectly activates the SMO co-receptor. The activated SMO leads to the formation of a multiprotein complex, GLI complex, considered a hallmark in Hh pathway activation. Further, the functioning of the GLI complex is mediated by transcription factors GLI1, GLI2 (activator of the complex), and GLI3 (inhibitor of the complex). The activated GLI complex gets translocated in the nucleus, where the GLI1 and GLI2 transcription factor gets upregulated and engages itself in the transcription process, causing metastasis, angiogenesis, and apoptosis, resulting in the development of TNBC [[23]]. The transcription process also enhances the expression of proteins responsible for metastasis (SNAIL), and angiogenesis (angiopoietin-1, and 2) [[24], [25]]. Moreover, SMO directly activates MYCN, which elevates the expression of transcription factors, FOXM 1 and cyclin D, leading to the proliferation of TNBC cells [[26]]. Furthermore, it was observed that the other transcription factors, namely NF-kB, FOXC1, and Hypoxia-induced factor (HIF)-1α are also involved in the deregulation of Hh signaling, along with TGF-β, RAS/MAPK (mitogen-activated protein kinases) signaling pathways, and the extracellular matrix protein osteopontin (OPN), thus, overall contributing to enhanced growth and invasion of TNBC [[27]]. It was reported by Mukherjee et al., 2006, that 70% of ductal carcinomas and 30% of metastatic breast cancer showed an overexpression of SMO receptors [[28]].

3. Wnt/β-Catenin Pathway

The Wnt signaling pathway serves a vital role in the patterning of embryonic tissue, migration of cells as well as its adhesion, maintenance of stem cells, and mediating epithelial-mesenchymal interactions [[10]]. This signaling pathway activates when Wnt proteins bind with LRP5/6 protein (LDL receptor-related protein5/6), and Frizzled protein (FZD; seven-pass transmembrane receptor protein) [[29]]. In absence of Wnt proteins/ligands, β-catenin is concealed within a complex comprising of axin, adenomatous polyposis coli (APC) tumor suppressor, glycogen synthase kinase-3β (GSK3β), and casein kinase 1 (CK1), which later triggers phosphorylation of β-catenin via CK1 and GSK3β and results in ubiquitination. This ubiquitination then compels the 26S proteasome to degrade β-catenin [[30]]. However, when Wnt proteins interact with LRP5/6 and FZD, they form a complex called the Wnt-LRP5/6-FZD complex, which inhibits GSK3β and leads to the cytosolic β-catenin stabilization. The free β-catenin then translocates from the cytoplasm to the nucleus, where it associates with T-cell factor (TCF)/lymphoid enhancing factor (LEF) to activate the expression of various downstream targeted genes that are responsible for regulating cell growth, proliferation, and apoptosis, thus mediating initiation as well as the progression of TNBC [[31]]. In a study, the up-regulated expression of FZD and LRP5/6 in TNBC cells was also observed. Also, TNBC cells exhibit a transcriptional knockdown of FZD/LRP6 that establishes its restraining activity in vivo. It was further generalized that the association of the Wnt/β-catenin pathway with the progression of TNBC is related either with a gain of nuclear β-catenin or loss of membranous β-catenin [[32]].

4. TGF-β Signaling Pathway

The TGF-β signaling pathway is a pathway involved in the growth of cells, their differentiation, homeostasis, as well as apoptosis. TGF-β cytokines are comprised of many members, out of which TGF-β1, encoded via TGF-β1 gene [[33],[34]] has been announced to play an essential part in breast cancer stem cells (BCSC). It was observed that the TGF-β receptor 1 (TGFBR1) is overexpressed in BCSC [[35]]. On further study, it was found that TGF-β1 induces EMT in mammary cells, which results in tumor formation [[36]]. This was further evidenced by a study performed by Sendurai et al., 2008, which exhibited that the mammary stem cells indicated increased expression of TGF-β1, thereby increasing their ability of mammospheres formation along with EMT gene expression like N- and E- cadherin, Slug, and Snail, associated with TNBC progression. On a similar note, Michael et al., 2011, reported that the CSCs (cancer stem cells) formed by TGF-β/TNFα induced EMT, showed enhanced self-renewing capacity along with increased tumorigenicity and chemotherapeutics resistance [[37]]. Also, the TGF-β1 pathway was found to generate SMAD2/3 and SMAD4 expression, causing activity like the synthesis of protein, growth proliferation, metastasis, and angiogenesis [[1]]. Thus, it could be inferred that TGF-β signaling plays a crucial character in the activation of EMT and procuring stemness, hence this pathway has been suggested as a novel therapeutic approach against TNBCs.

5. PI3K/AKT/mTOR Signaling Pathway

PI3Ks are considered an important molecule of the PI3K/AKT/mTOR signaling cascade that lead to the growth of tumor cells. PI3Ks are heterodimers composed of p85 (regulatory subunit), and p110 (catalytic subunit). There are four PI3Ks isoforms currently known, namely α, β, ϒ, and δ [[38]]. PI3K/AKT/mTOR signaling pathway gets activated when stimulated by tyrosine kinases receptor, which further causes activation of PI3K, followed by AKT and mTORC1 phosphorylation [[39]]. The mTOR is a kinase protein composed of serine/threonine, responsible for controlling cellular proliferation, cellular growth, motility, and survival, as well as protein synthesis and transcription [[40],[41]]. mTOR is comprised of two complexes, namely mTORC1 and mTORC2. It was found that both mTORC1 and mTORC2 induce S-phase kinase association protein, which leads to the synthesis of protein, growth, and proliferation of cells along with metastasis and angiogenesis. Hence, the progression of TNBC is found to be associated with the deregulation of the mTOR pathway [[1]]. It was further observed from the studies that in TNBC, the actuation of the PI3K/AKT/mTOR signaling pathway was also mediated via overexpression of EGFR (upstream regulators), and proline-rich inositol polyphosphatase (downstream regulator), mutation of the PIK3Cα, and loss of expression of PTEN [ [42],[43], [44]]. Further, it was observed that the inactivation of p53 protein unleashes various tumorigenic pathways like FGFR (fibroblast growth factor receptor), cMET, and RAF (rapidly accelerated fibrosarcoma) kinases, which then activates the PI3K/AKT/mTOR signaling pathway [[45]]. However, TNBC progression was found to be rare when termed with the mutation of other downstream regulators of PI3K/AKT/mTOR signaling pathway (AkT, and mTOR) as well as cognate pathway (RAS, and MAPK) [[46]]. Thus, it could be inferred that the PI3K/AKT/mTOR signaling pathway can be used as a potential target of TNBCs.

6. EGFR

EGFR is a transmembrane tyrosine kinase receptor, belonging to the family of HER/erythroblastosis virus oncogene B (ErbB) [[47],[48]]. EGFR is responsible for regulating cell proliferation, cell differentiation, cellular invasion along with angiogenesis and apoptosis. Also, EGFR regulates the expression of Akt (PKB) and MAPK, responsible for inducing drug resistance [[49],[50]]. Initially, EGFR was regarded as a target of lung cancer only, however, through recent studies it was revealed that EGFR also plays a role in the progression of TNBC [[50]]. It was revealed in a study that unlike the mutation of EGFR in the case of lung cancer, the progression of TNBC is related to an increased number of EGFR genes, and not the mutation of EGFR [[51]]. EGFR-overexpressing TNBCs were regarded as basal-like high-grade carcinomas. On the binding of BRCA1 to the miR-146a promoter, there occurs an increase in miR-146a transcriptional levels, which allows the binding of miR-146a to the 3’UTR of EGFR for promoting the degradation of its mRNA. As the TNBC is related to the EGFR gene number, it could be stated that the deficiency of BRCA1 and miR-146a prevents the degradation of mRNA, which in turn increases the number of gene expressions of EGFR and p-EGFR (Y1068) [[52],[53]]. It was found that approximately 36% to 89% of TNBC showed an overexpression of EGFR. Further, it was observed that the survival of disease-free patients of TNBC patients is negatively associated with the overexpression of the EGFR gene [[51],[53],[54]]. Hence, it is reflected that EGFR can serve as a potential target for TNBC therapy.

7. IGF1R

In a clinical study, it was found that 50–75% of TNBCs showed enhanced expression of the IGF1R. IGF1R causes growth, invasion, as well as metastasis in patients suffering from TNBC. It has been reported that IGF1R increases the metastasis in cancer cells by inducing anchorage-independent growth, which became evident from a pre-clinical trial that showed an over-expression of IGF1R in the tumor initiation site as well as in the site where metastasis took place. Further, it was observed that IGF1R also inhibits the apoptosis caused due to the administration of the chemotherapeutic drug, hence suggesting an incidence of chemo-resistance [[55]].

8. PARP1

PARP1 belongs to the class of DNA repair enzymes, and plays a vital character in managing genomic stability, DNA repairing, regulating the progression of the cell cycle, and apoptosis [[56]]. PARP1 responds to single-stranded DNA damage via various repairing mechanisms like base excision repair mechanism, nucleotide excision repair mechanism, or mismatch repair mechanism and hence maintains the genomic integrity [[57]]. Hence, it could be stated that PARP1 inhibition causes loss of DNA repair functioning, inducing apoptosis [[57]].
On a similar note, it was observed that in the absence of the PARP1 enzyme, an aggregation of single-strand breaks (ssDNA) occurs, resulting in the generation of double-strand breaks (dsDNA), which were then repaired by homologous recombination (HR). HR is an error-free repairing process involving BRAC1 and BRAC2 proteins. So, the presence of PARP1 inhibits the functioning of HR, causing mutations in BRAC proteins [[58]], and from various studies, it was found that ≈70% of mutated BRCA1 and ≈16–23% of mutated BRCA2 breast cancers are regarded as TNBCs [[59]]. Therefore, inhibition of the PARP1 enzyme can also be used as a target in TNBC therapy.

9. Src Kinases

Src is a tyrosine kinase protein of the non-receptor type that belongs to the Src family kinases (SFKs). Src gets activated by two means, either via cytoplasmic proteins like focal adhesion kinase (FAK), Crk-associated substrate (CAS), playing a distinct role in integrin signaling, or via activation of ligand belonging to cell-surface receptors like EGFR, FGFR, VEGFR, etc. It was observed that SRCs regulate various signal transduction pathways associated with cell adhesion, cell migration, invasion, and angiogenesis [[60]]. In a study, it was found that TNBC is associated with overexpression of c-SRC kinases, also known as proto-oncogene tyrosine-protein kinase Src. The overexpression of c-Src in TNBC is responsible for tumorigenic proliferation, migration, and invasion [[61], [62]111,112]. Also, c-Src overexpression facilitates bone metastases in the case of metastatic TNBC. It was found that the increased activity of Src kinase is either due to its increased transcription or due to its deregulation caused by the overexpression of the upstream growth factor receptors including EGFR, PDGFR, FGFR, VEGFR, integrin, FAK, etc. [[60]].

10. Immune-System Targeting

Immune checkpoint inhibitors like anti-PD-1, anti-PD-L1, and anti-CTLA-4 demonstrate a novel type of immunotherapy for the treatment of cancer. It was found that in cancer progression, the immune response gets compromised. Research evidence revealed that T-lymphocytes are responsible for activating the distinct immune responses against an emerging antigen. Further, it was observed that lymphocyte surface receptors get stimulated when interacting with an antigen-presenting cell (APC) [[63]]. Cell activation needs definite identification of the presented antigen, as well as a specific signal from co-stimulators that are mobilized during the generation of the immune synapse. Such cell effector functions are inhibited by signals produced by negative cell receptors. The stated mechanism is anticipated to prevent the undesirable effects of overstimulation, causing an autoreactive response or stimulation of carcinogenesis once the defensive role of the lymphocyte antigen is swept. PD-1 (CD279) belongs to such type of negative receptor. Similar to PD-1, CTLA-4 is also a negative receptor available on APC, which on binding with CD80-B7-1, and CD86-B7-2 ligands activates an inhibitory reaction, which suppresses the immune responses, blocks the responses of T-lymphocytes, decreases the T-lymphocyte proliferation, and limits the secretion of cytokine. All of these contribute to an immune deficiency in cancer patients [[64]].
Hence, it was suggested that immunotherapy deals with the unblocking of the suppressed immune system and activating the functioning of T-lymphocyte within the lymph node, which gets translated to an effective immune response against TNBC.

10.1. PD-L1

Programmed cell death (PD-1) receptor along with its ligand PD-L1 have been identified as biomarkers, because they are overexpressed in TNBC more than in any other type of breast cancer [[65],[66]]. The concept of immunotherapy lies in the fact that sometimes cancerous cells escape recognition as well as avoid destruction from the host immune system because of the immune checkpoint system, which provides ample opportunities for the cancerous cells to grow, migrate, invade, proliferate, and metastasize. In such cases, immunotherapy plays a vital part in blocking the immune checkpoint system, thus providing a therapeutic and effective antitumor immunity [[67]].
PD-1 is an inhibitory receptor belonging to the family of B7-CD28. PD-1 is overexpressed on the activated lymphocytes, non-lymphocytic cells like activated monocytes and dendritic cells, B-cells, and natural killer cells [[68]]. PD-1 is comprised of two ligands, PD-L1, and PD-L2, out of which PD-L1 is overexpressed in cancer cells, tumor-infiltrating lymphocytes, fibroblasts, and macrophages [[68], [69]]. In one of the studies, it was observed that statistically, about 45% of patients suffering from TNBC showed enhanced upregulation of both PD-L1 and PD-1, while 59% showed overexpression of PD-L1, and 70% showed overexpression of PD-1 [[70],[71]]. It was observed that the interaction of PD-1 to PD-L1, made the T-cells less active and form an inhibitory state, which provides a reduced immune response towards foreign antigens. This mechanism proved profitable to normal cells in preserving an immune balance and preventing an autoimmune response. However, this mechanism can lead to the detection of tumor cell evasion and elimination induced by the immune system [[72]]. Hence, it could be indicated that the PD-L1 positivity can be considered a TNBC biomarker that could be targeted via immune checkpoint inhibitor for better therapeutic response [[73]].

10.2. CTLA-4

CTLA-4 is an inhibitory receptor of T-cell, which is found to be overexpressed on activated CD8+ T cells [[74]]. Like PD-L, CTLA-4 also restricts the activation of T-cells by preventing its binding with its co-stimulatory molecules like CD80, and CD 86, resulting in detection of tumor cell evasion as well as its elimination by the immune system [[75]]. Hence, CTLA-4 also acts as a potential target against TNBC.

11. CSPG4 Proteins

CSPG4 is a proteoglycan, situated on the cell surface and found to be overexpressed in both melanoma cells and TNBC cells. It is also referred to as a melanoma-associated antigen or melanoma chondroitin sulfate proteoglycan [[76]]. CSPG4 protein spreads over the endothelial basement membrane, stabilizing the interaction between cell-substratum and resulting in events like cellular growth and proliferation, angiogenesis, and metastasis [[77]].

12. Androgen Receptor (AR)

ARs belong to the family of nuclear steroid hormone receptors [[78]]. The activation of AR is conducted by either the ERK-dependent pathway or the ERK-independent pathway. The ERK-dependent pathway includes the interaction of cytoplasmic AR with proteins like PI3K, Ras GTPase, and Src proteins, whereas the ERK-independent pathway involves phosphorylation of mTOR, activation of PKA, and inactivation of forkhead box protein O1 (FOXO1). Both the activation pathways ultimately result in cellular proliferation, EMT, angiogenesis, and metastasis [[79],[80]]. It was observed in a clinical study that 25–75% of TNBC progression is due to overexpression of AR, mostly in the LAR subtype of TNBC [[81],[82]]. In ASCO annual meeting, 2017, an investigation on AR expression in patients with TNBC showed that ≈30% of the patients were found to have positive AR expression [[37]]. Hence, it is contemplated that targeting AR may provide a potential platform for the treatment of TNBC.
Hence, from the above findings, it was observed that before providing proper treatment, one must identify the targets, which may be either proteins (CSPG4, Src Kinases), signaling pathways (Notch, hedgehog, Wnt-β, TGF-β, PI3K/AKT/mTOR), receptors (EGFR, IGF1R, AR, PD-1, CTLA-4) or enzymes (PARP1). It was observed that deregulation of these targets leads to TNBC progression. So, if one can identify those targets responsible for the progression, then their deregulation can be restricted or minimized, which will further reduce the risk of cancer growth. Moreover, based on the identifiable targets, various novel treatment options are under development. 

References

  1. Vinayak S. Jamdade; Nikunj Sethi; Nitin A. Mundhe; Parveen Kumar; Mangala Lahkar; Neeraj Sinha; Therapeutic targets of triple-negative breast cancer: a review. British Journal of Pharmacology 2015, 172, 4228-4237, 10.1111/bph.13211.
  2. Gabriela Dontu; Kyle W Jackson; Erin McNicholas; Mari J Kawamura; Wissam M Abdallah; Max S Wicha; Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells. Breast Cancer Research 2004, 6, 1-11, 10.1186/bcr920.
  3. Robert B. Clarke; Katherine Spence; Elizabeth Anderson; Anthony Howell; Hideyuki Okano; Christopher S. Potten; A putative human breast stem cell population is enriched for steroid receptor-positive cells. Developmental Biology 2005, 277, 443-456, 10.1016/j.ydbio.2004.07.044.
  4. Ie-Ming Shih; Tian-Li Wang; Notch Signaling, Gamma Secretase Inhibitors, and Cancer Therapy. Cancer Research 2007, 67, 1879-1882, 10.1158/0008-5472.can-06-3958.
  5. Christel Brou; Frédérique Logeat; Neetu Gupta-Rossi; Christine Bessia; Odile LeBail; John R Doedens; Ana Cumano; Pascal Roux; Roy A Black; Alain Israël; et al. A Novel Proteolytic Cleavage Involved in Notch Signaling: The Role of the Disintegrin-Metalloprotease TACE. Molecular Cell 2000, 5, 207-216, 10.1016/s1097-2765(00)80417-7.
  6. Jeff Mumm; Eric H Schroeter; Meera T Saxena; Adam Griesemer; Xiaolin Tian; D.J Pan; William Ray; Raphael Kopan; A Ligand-Induced Extracellular Cleavage Regulates γ-Secretase-like Proteolytic Activation of Notch1. Molecular Cell 2000, 5, 197-206, 10.1016/s1097-2765(00)80416-5.
  7. Sanjiv Shah; Sheu-Fen Lee; Katsuhiko Tabuchi; Yi-Heng Hao; Cong Yu; Quincey LaPlant; Haydn Ball; Charles E. Dann; Thomas Südhof; Gang Yu; et al. Nicastrin Functions as a γ-Secretase-Substrate Receptor. Cell 2005, 122, 435-447, 10.1016/j.cell.2005.05.022.
  8. Wendy Gordon; Kelly Arnett; Stephen C. Blacklow; The molecular logic of Notch signaling – a structural and biochemical perspective. Journal of Cell Science 2008, 121, 3109-3119, 10.1242/jcs.035683.
  9. R A Kovall; More complicated than it looks: assembly of Notch pathway transcription complexes. Oncogene 2008, 27, 5099-5109, 10.1038/onc.2008.223.
  10. Sandra A O'toole; Jane M Beith; E. K. A. Millar; Richard West; Anna McLean; Aurelie Cazet; Alexander Swarbrick; Samantha R Oakes; Therapeutic targets in triple negative breast cancer. Journal of Clinical Pathology 2013, 66, 530-542, 10.1136/jclinpath-2012-201361.
  11. Salvatore Pece; Michela Serresi; Elisa Santolini; Maria Capra; Esther Hulleman; Viviana Galimberti; Stefano Zurrida; Patrick Maisonneuve; Giuseppe Viale; Pier Paolo Di Fiore; et al. Loss of negative regulation by Numb over Notch is relevant to human breast carcinogenesis. Journal of Cell Biology 2004, 167, 215-221, 10.1083/jcb.200406140.
  12. Suling Liu; Gabriela Dontu; Max S Wicha; Mammary stem cells, self-renewal pathways, and carcinogenesis. Breast Cancer Research 2005, 7, 86-95, 10.1186/bcr1021.
  13. Jodi Speiser; Kimberly Foreman; Eva Drinka; Constantine Godellas; Claudia Perez; Alia Salhadar; Çağatay Erşahin; Prabha Rajan; Notch-1 and Notch-4 Biomarker Expression in Triple-Negative Breast Cancer. International Journal of Surgical Pathology 2011, 20, 137-143, 10.1177/1066896911427035.
  14. Shanchun Guo; Mingli Liu; Ruben R. Gonzalez-Perez; Role of Notch and its oncogenic signaling crosstalk in breast cancer. Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms 2011, 1815, 197-213, 10.1016/j.bbcan.2010.12.002.
  15. H Ling; J-R Sylvestre; P Jolicoeur; Notch1-induced mammary tumor development is cyclin D1-dependent and correlates with expansion of pre-malignant multipotent duct-limited progenitors. Oncogene 2010, 29, 4543-4554, 10.1038/onc.2010.186.
  16. Argiris Efstratiadis; Matthias Szabolcs; Apostolos Klinakis; Notch, Myc and Breast Cancer. Cell Cycle 2007, 6, 418-429, 10.4161/cc.6.4.3838.
  17. Irene Graziani; Sandra Eliasz; Melissa A. De Marco; Yuanbin Chen; Harvey Pass; Richard M. De May; Peter Strack; Lucio Miele; Maurizio Bocchetta; Opposite Effects of Notch-1 and Notch-2 on Mesothelioma Cell Survival under Hypoxia Are Exerted through the Akt Pathway. Cancer Research 2008, 68, 9678-9685, 10.1158/0008-5472.can-08-0969.
  18. Norman Fultang; Madhuparna Chakraborty; Bela Peethambaran; Regulation of cancer stem cells in triple negative breast cancer. Cancer Drug Resistance 2021, 4, 321-342, 10.20517/cdr.2020.106.
  19. Karin Rennstam; Nicole McMichael; Pontus Berglund; Gabriella Honeth; Cecilia Hegardt; Lisa Rydén; Lena Luts; Pär-Ola Bendahl; Ingrid Hedenfalk; Numb protein expression correlates with a basal-like phenotype and cancer stem cell markers in primary breast cancer. Breast Cancer Research and Treatment 2009, 122, 315-324, 10.1007/s10549-009-0568-x.
  20. D Gallahan; R Callahan; Mammary tumorigenesis in feral mice: identification of a new int locus in mouse mammary tumor virus (Czech II)-induced mammary tumors. Journal of Virology 1987, 61, 66-74, 10.1128/jvi.61.1.66-74.1987.
  21. Kristen M. Reipas; Jennifer H. Law; Nicole Couto; Sumaiya Islam; Yvonne Li; Huifang Li; Artem Cherkasov; Karen Jung; Amarpal Cheema; Steven Jones; et al.John A. HassellSandra E. Dunn Luteolin is a novel p90 ribosomal S6 kinase (RSK) inhibitor that suppresses Notch4 signaling by blocking the activation of Y-box binding protein-1 (YB-1). Oncotarget 2013, 4, 329-345, 10.18632/oncotarget.834.
  22. Michael T. Lewis; Jacqueline M. Veltmaat; Next Stop, the Twilight Zone: Hedgehog Network Regulation of Mammary Gland Development. Journal of Mammary Gland Biology and Neoplasia 2004, 9, 165-181, 10.1023/b:jomg.0000037160.24731.35.
  23. Akil A. Merchant; William Matsui; Targeting Hedgehog- A Cancer Stem Cell Pathway. Clinical Cancer Research 2010, 16, 3130-3140, 10.1158/1078-0432.ccr-09-2846.
  24. Joyce G. Habib; Joyce A. O'shaughnessy; The hedgehog pathway in triple‐negative breast cancer. Cancer Medicine 2016, 5, 2989-3006, 10.1002/cam4.833.
  25. Akil A. Merchant; William Matsui; Targeting Hedgehog — a Cancer Stem Cell Pathway. Clinical Cancer Research 2010, 16, 3130-3140, 10.1158/1078-0432.ccr-09-2846.
  26. William R Polkinghorn; Nancy J Tarbell; Medulloblastoma: tumorigenesis, current clinical paradigm, and efforts to improve risk stratification. Nature Clinical Practice Oncology 2007, 4, 295-304, 10.1038/ncponc0794.
  27. Joyce G. Habib; Joyce A. O'shaughnessy; The hedgehog pathway in triple‐negative breast cancer. Cancer Medicine 2016, 5, 2989-3006, 10.1002/cam4.833.
  28. Shibani Mukherjee; Natalya Frolova; Andrea Sadlonova; Zdenek Novak; Adam Steg; Grier Page; Danny R. Welch; Susan M. Lobo-Ruppert; J. Michael Ruppert; Martin R. Johnson; et al.Andra R. Frost Hedgehog signaling and response to cyclopamine differs in epithelial and stromal cells in benign breast and breast cancer. Cancer Biology & Therapy 2006, 5, 674-683, 10.4161/cbt.5.6.2906.
  29. Taj D. King; Mark J. Suto; Yonghe Li; The wnt/β-catenin signaling pathway: A potential therapeutic target in the treatment of triple negative breast cancer. Journal of Cellular Biochemistry 2011, 113, 13-18, 10.1002/jcb.23350.
  30. Julia Izrailit; Michael Reedijk; Developmental pathways in breast cancer and breast tumor-initiating cells: Therapeutic implications. Cancer Letters 2012, 317, 115-126, 10.1016/j.canlet.2011.11.028.
  31. Wenyan Lu; Cuihong Lin; Michael J. Roberts; William R. Waud; Gary Piazza; Yonghe Li; Niclosamide Suppresses Cancer Cell Growth By Inducing Wnt Co-Receptor LRP6 Degradation and Inhibiting the Wnt/β-Catenin Pathway. PLOS ONE 2011, 6, e29290, 10.1371/journal.pone.0029290.
  32. Felipe C Geyer; Magali Lacroix-Triki; Kay Savage; Monica Arnedos; Maryou B Lambros; Alan Mackay; Rachael Natrajan; Jorge S Reis-Filho; β-Catenin pathway activation in breast cancer is associated with triple-negative phenotype but not with CTNNB1 mutation. Modern Pathology 2010, 24, 209-231, 10.1038/modpathol.2010.205.
  33. Mohsen Ghadami; Yoshio Makita; Kunihiro Yoshida; Gen Nishimura; Yoshimitsu Fukushima; Keiko Wakui; Shiro Ikegawa; Koki Yamada; Shinji Kondo; Norio Niikawa; et al.Hiroaki Tomita Genetic Mapping of the Camurati-Engelmann Disease Locus to Chromosome 19q13.1-q13.3. The American Journal of Human Genetics 2000, 66, 143-147, 10.1086/302728.
  34. Stacia P. Vaughn; Sherrice Broussard; Catherine Rhoades Hall; Allison Scott; Susan H. Blanton; Jeff M. Milunsky; Jacqueline T. Hecht; Confirmation of the Mapping of the Camurati–Englemann Locus to 19q13.2 and Refinement to a 3.2-cM Region. Genomics 2000, 66, 119-121, 10.1006/geno.2000.6192.
  35. Neil E. Bhola; Justin M. Balko; Teresa C. Dugger; María Gabriela Kuba; Violeta Sánchez; Melinda Sanders; Jamie Stanford; Rebecca S. Cook; Carlos L. Arteaga; TGF-β inhibition enhances chemotherapy action against triple-negative breast cancer. Journal of Clinical Investigation 2013, 123, 1348-1358, 10.1172/jci65416.
  36. Sendurai A. Mani; Wenjun Guo; Mai-Jing Liao; Elinor Ng. Eaton; Ayyakkannu Ayyanan; Alicia Zhou; Mary Brooks; Ferenc Reinhard; Cheng Cheng Zhang; Michail Shipitsin; et al.Lauren L. CampbellKornelia PolyakCathrin BriskenJing YangRobert A. Weinberg The Epithelial-Mesenchymal Transition Generates Cells with Properties of Stem Cells. Cell 2008, 133, 704-715, 10.1016/j.cell.2008.03.027.
  37. Fangyuan Shao; Heng Sun; Chu-Xia Deng; Potential therapeutic targets of triple-negative breast cancer based on its intrinsic subtype. Oncotarget 2017, 8, 73329-73344, 10.18632/oncotarget.20274.
  38. Patricia Mucci Lorusso; Inhibition of the PI3K/AKT/mTOR Pathway in Solid Tumors. Journal of Clinical Oncology 2016, 34, 3803-3815, 10.1200/jco.2014.59.0018.
  39. Ricardo L. B. Costa; Hyo Sook Han; William J. Gradishar; Targeting the PI3K/AKT/mTOR pathway in triple-negative breast cancer: a review. Breast Cancer Research and Treatment 2018, 169, 397-406, 10.1007/s10549-018-4697-y.
  40. Nissim Hay; Nahum Sonenberg; Upstream and downstream of mTOR. Genes & Development 2004, 18, 1926-1945, 10.1101/gad.1212704.
  41. Christopher S. Beevers; Fengjun Li; Lei Liu; Shile Huang; Curcumin inhibits the mammalian target of rapamycin-mediated signaling pathways in cancer cells. International Journal of Cancer 2006, 119, 757-764, 10.1002/ijc.21932.
  42. Tongrui Liu; Rami Yacoub; LaTonia D. Taliaferro-Smith; Shi-Yong Sun; Tisheeka R. Graham; Ryan Dolan; Christine Lobo; Mourad Tighiouart; Lily Yang; Amy Adams; et al.Ruth M. O'regan Combinatorial Effects of Lapatinib and Rapamycin in Triple-Negative Breast Cancer Cells. Molecular Cancer Therapeutics 2011, 10, 1460-1469, 10.1158/1535-7163.mct-10-0925.
  43. Paolo Cossu-Rocca; Sandra Orrù; Maria Rosaria Muroni; Francesca Sanges; Giovanni Sotgiu; Sara Ena; Giovanna Pira; Luciano Murgia; Alessandra Manca; Maria Gabriela Uras; et al.Maria Giuseppina SarobbaSilvana UrruMaria Rosaria De Miglio Analysis of PIK3CA Mutations and Activation Pathways in Triple Negative Breast Cancer. PLoS ONE 2015, 10, e0141763, 10.1371/journal.pone.0141763.
  44. Lisa M. Ooms; Lauren C. Binge; Elizabeth M. Davies; Parvin Rahman; James R.W. Conway; Rajendra Gurung; Daniel T. Ferguson; Antonella Papa; Clare G. Fedele; Jessica L. Vieusseux; et al.Ryan C. ChaiFrank KoentgenJohn T. PriceTony TiganisPaul TimpsonCatriona A. McLeanChristina A. Mitchell The Inositol Polyphosphate 5-Phosphatase PIPP Regulates AKT1-Dependent Breast Cancer Growth and Metastasis. Cancer Cell 2015, 28, 155-169, 10.1016/j.ccell.2015.07.003.
  45. Hui Liu; Charles J. Murphy; Florian A. Karreth; Kristina B. Emdal; Forest M. White; Olivier Elemento; Alex Toker; Gerburg M. Wulf; Lewis C. Cantley; Identifying and Targeting Sporadic Oncogenic Genetic Aberrations in Mouse Models of Triple-Negative Breast Cancer. Cancer Discovery 2017, 8, 354-369, 10.1158/2159-8290.cd-17-0679.
  46. Joycelyn Jie Xin Lee; Kiley Loh; Yoon-Sim Yap; PI3K/Akt/mTOR inhibitors in breast cancer. Cancer Biology & Medicine 2015, 12, 342-354, 10.7497/j.issn.2095-3941.2015.0089.
  47. Roy S Herbst; Review of epidermal growth factor receptor biology. International Journal of Radiation Oncology*Biology*Physics 2004, 59, S21-S26, 10.1016/j.ijrobp.2003.11.041.
  48. Hongtao Zhang; Alan Berezov; Qiang Wang; Geng Zhang; Jeffrey Drebin; Ramachandran Murali; Mark I. Greene; ErbB receptors: from oncogenes to targeted cancer therapies. Journal of Clinical Investigation 2007, 117, 2051-2058, 10.1172/jci32278.
  49. Mona L. Gauthier; Cheryl Torretto; John Ly; Valerie Francescutti; Danton H. O’Day; Protein kinase Cα negatively regulates cell spreading and motility in MDA-MB-231 human breast cancer cells downstream of epidermal growth factor receptor. Biochemical and Biophysical Research Communications 2003, 307, 839-846, 10.1016/s0006-291x(03)01273-7.
  50. Yuval Tabach; Michael Milyavsky; Igor Shats; Ran Brosh; Or Zuk; Assif Yitzhaky; Roberto Mantovani; Eytan Domany; Varda Rotter; Yitzhak Pilpel; et al. The promoters of human cell cycle genes integrate signals from two tumor suppressive pathways during cellular transformation. Molecular Systems Biology 2005, 1, 2005.0022-2005.0022, 10.1038/msb4100030.
  51. Heae Surng Park; Min Hye Jang; Eun Joo Kim; Hyun Jeong Kim; Hee Jin Lee; Yu Jung Kim; Jee Hyun Kim; Eunyoung Kang; Sung-Won Kim; In Ah Kim; et al.So Yeon Park High EGFR gene copy number predicts poor outcome in triple-negative breast cancer. Modern Pathology 2014, 27, 1212-1222, 10.1038/modpathol.2013.251.
  52. E Kumaraswamy; K L Wendt; L A Augustine; S R Stecklein; E C Sibala; D Li; S Gunewardena; R A Jensen; BRCA1 regulation of epidermal growth factor receptor (EGFR) expression in human breast cancer cells involves microRNA-146a and is critical for its tumor suppressor function. Oncogene 2014, 34, 4333-4346, 10.1038/onc.2014.363.
  53. Katsuya Nakai; Mien-Chie Hung; Hirohito Yamaguchi; A perspective on anti-EGFR therapies targeting triple-negative breast cancer.. American journal of cancer research 2016, 6, 1609-23.
  54. Arathi A Changavi; Arundhathi Shashikala; Ashwini S Ramji; Epidermal Growth Factor Receptor Expression in Triple Negative and Nontriple Negative Breast Carcinomas. Journal of Laboratory Physicians 2015, 7, 079-083, 10.4103/0974-2727.163129.
  55. Rebecca Johnson; Nirupama Sabnis; Walter J. McConathy; Andras G. Lacko; The Potential Role of Nanotechnology in Therapeutic Approaches for Triple Negative Breast Cancer. Pharmaceutics 2013, 5, 353-370, 10.3390/pharmaceutics5020353.
  56. Lucio Tentori; Grazia Graziani; Chemopotentiation by PARP inhibitors in cancer therapy. Pharmacological Research 2005, 52, 25-33, 10.1016/j.phrs.2005.02.010.
  57. Mike De Vos; Valérie Schreiber; Françoise Dantzer; The diverse roles and clinical relevance of PARPs in DNA damage repair: Current state of the art. Biochemical Pharmacology 2012, 84, 137-146, 10.1016/j.bcp.2012.03.018.
  58. Jill J. J. Geenen; Sabine C. Linn; Jos H. Beijnen; Jan H. M. Schellens; PARP Inhibitors in the Treatment of Triple-Negative Breast Cancer. Clinical Pharmacokinetics 2017, 57, 427-437, 10.1007/s40262-017-0587-4.
  59. Soo-Yeon Hwang; Seojeong Park; Youngjoo Kwon; Recent therapeutic trends and promising targets in triple negative breast cancer. Pharmacology & Therapeutics 2019, 199, 30-57, 10.1016/j.pharmthera.2019.02.006.
  60. R. S. Finn; Targeting Src in breast cancer. Annals of Oncology 2008, 19, 1379-1386, 10.1093/annonc/mdn291.
  61. D. Tryfonopoulos; S. Walsh; Denis Collins; L. Flanagan; C. Quinn; B. Corkery; E. W. McDermott; D. Evoy; A. Pierce; N. O’Donovan; et al.J. CrownM. J. Duffy Src: a potential target for the treatment of triple-negative breast cancer. Annals of Oncology 2011, 22, 2234-2240, 10.1093/annonc/mdq757.
  62. María Pilar Sánchez-Bailón; Annarica Calcabrini; Daniel Gómez-Domínguez; Beatriz Morte; Esther Martín-Forero; Gonzalo Gómez López; Agnese Molinari; Kay-Uwe Wagner; Jorge Martín-Pérez; Src kinases catalytic activity regulates proliferation, migration and invasiveness of MDA-MB-231 breast cancer cells. Cellular Signalling 2012, 24, 1276-1286, 10.1016/j.cellsig.2012.02.011.
  63. Harshad Harde; Krupa Siddhapura; Ashish Kumar Agrawal; Sanyog Jain; Development of dual toxoid-loaded layersomes for complete immunostimulatory response following peroral administration. Nanomedicine 2015, 10, 1077-1091, 10.2217/nnm.14.177.
  64. Marek Z. Wojtukiewicz; Magdalena M. Rek; Kamil Karpowicz; Maria Górska; Barbara Polityńska; Anna M. Wojtukiewicz; Marcin Moniuszko; Piotr Radziwon; Stephanie C. Tucker; Kenneth V. Honn; et al. Inhibitors of immune checkpoints—PD-1, PD-L1, CTLA-4—new opportunities for cancer patients and a new challenge for internists and general practitioners. Cancer and Metastasis Reviews 2021, 40, 949-982, 10.1007/s10555-021-09976-0.
  65. Guy Jerusalem; Joelle Collignon; Helene Schroeder; Laurence Lousberg; Triple-negative breast cancer: treatment challenges and solutions. Breast Cancer: Targets and Therapy 2016, 8, 93-107, 10.2147/bctt.s69488.
  66. Hongyan Jia; Cristina I. Truica; Bin Wang; Yanhong Wang; Xingcong Ren; Harold A. Harvey; Jianxun Song; Jin-Ming Yang; Immunotherapy for triple-negative breast cancer: Existing challenges and exciting prospects. Drug Resistance Updates 2017, 32, 1-15, 10.1016/j.drup.2017.07.002.
  67. Y. Ishida; Y. Agata; K. Shibahara; T. Honjo; Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death.. The EMBO Journal 1992, 11, 3887-3895, 10.1002/j.1460-2075.1992.tb05481.x.
  68. Mary E. Keir; Manish J. Butte; Gordon J. Freeman; Arlene H. Sharpe; PD-1 and Its Ligands in Tolerance and Immunity. Annual Review of Immunology 2008, 26, 677-704, 10.1146/annurev.immunol.26.021607.090331.
  69. Ashley Cimino-Mathews; Elizabeth Thompson; Janis M. Taube; Xiaobu Ye; Yao Lu; Alan Meeker; Haiying Xu; Rajni Sharma; Kristen Lecksell; Toby Cornish; et al.Nathan CukaPedram ArganiLeisha A. Emens PD-L1 (B7-H1) expression and the immune tumor microenvironment in primary and metastatic breast carcinomas. Human Pathology 2015, 47, 52-63, 10.1016/j.humpath.2015.09.003.
  70. Parham Khosravi-Shahi; Luis Cabezón-Gutiérrez; Sara Custodio-Cabello; Metastatic triple negative breast cancer: Optimizing treatment options, new and emerging targeted therapies. Asia-Pacific Journal of Clinical Oncology 2017, 14, 32-39, 10.1111/ajco.12748.
  71. Zoran Gatalica; Carrie Snyder; Todd Maney; Anatole Ghazalpour; Daniel A. Holterman; Nianqing Xiao; Peggy Overberg; Inga Rose; Gargi D. Basu; Semir Vranic; et al.Henry T. LynchDaniel D. Von HoffOmid Hamid Programmed Cell Death 1 (PD-1) and Its Ligand (PD-L1) in Common Cancers and Their Correlation with Molecular Cancer Type. Cancer Epidemiology Biomarkers & Prevention 2014, 23, 2965-2970, 10.1158/1055-9965.epi-14-0654.
  72. Mira Akiki; Fady Gh Haddad; Hampig Raphael Kourie; Abir Khaddage; Viviane Track Smayra; PD-L1: an unavoidable biomarker in advanced triple-negative breast cancer. Biomarkers in Medicine 2019, 13, 1539-1541, 10.2217/bmm-2019-0344.
  73. Peter Schmid; Sylvia Adams; Hope S. Rugo; Andreas Schneeweiss; Carlos H. Barrios; Hiroji Iwata; Véronique Diéras; Roberto Hegg; Seock-Ah IMpassion130 Trial Investigators; Gail Shaw Wright; et al.Volkmar HenschelLuciana MolineroStephen Y. ChuiRoel FunkeAmreen HusainEric P. WinerSherene LoiLeisha A. Emens Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. New England Journal of Medicine 2018, 379, 2108-2121, 10.1056/nejmoa1809615.
  74. Elizabeth A. Mittendorf; Anne V. Philips; Funda Meric-Bernstam; Na Qiao; Yun Wu; Susan Harrington; Xiaoping Su; Ying Wang; Ana M. Gonzalez-Angulo; Argun Akcakanat; et al.Akhil ChawlaMichael CurranPatrick HwuPadmanee SharmaJennifer K. LittonJeffrey J. MolldremGheath Alatrash PD-L1 Expression in Triple-Negative Breast Cancer. Cancer Immunology Research 2014, 2, 361-370, 10.1158/2326-6066.cir-13-0127.
  75. H. Mao; L. Zhang; Y. Yang; W. Zuo; Y. Bi; W. Gao; B. Deng; J. Sun; Q. Shao; Xun Qu; et al. New insights of CTLA-4 into its biological function in breast cancer.. Current Cancer Drug Targets 2010, 10, 728-736, 10.2174/156800910793605811.
  76. X. Wang; Y. Wang; L. Yu; K. Sakakura; C. Visus; J.H. Schwab; C.R. Ferrone; Elvira Favoino; Y. Koya; M.R. Campoli; et al.J.B. McCarthyA.B. DeLeoS. Ferrone CSPG4 in Cancer: Multiple Roles. Current Molecular Medicine 2010, 10, 419-429, 10.2174/156652410791316977.
  77. Xinhui Wang; Akihiro Katayama; Yangyang Wang; Ling Yu; Elvira Favoino; Koichi Sakakura; Alessandra Favole; Takahiro Tsuchikawa; Susan Silver; Simon Watkins; et al.Toshiro KageshitaSoldano Ferrone Functional Characterization of an scFv-Fc Antibody that Immunotherapeutically Targets the Common Cancer Cell Surface Proteoglycan CSPG4. Cancer Research 2011, 71, 7410-7422, 10.1158/0008-5472.can-10-1134.
  78. A.K. Roy; Y. Lavrovsky; C.S. Song; S. Chen; M.H. Jung; N.K. Velu; B.Y. Bi; B. Chatterjee; Regulation of Androgen Action. Klotho 1998, 55, 309-352, 10.1016/s0083-6729(08)60938-3.
  79. Elisabetta Pietri; Vincenza Conteduca; Daniele Andreis; Ilaria Massa; Elisabetta Melegari; Samanta Sarti; Lorenzo Cecconetto; Alessio Schirone; Sara Bravaccini; Patrizia Serra; et al.Anna FedeliRoberta MaltoniDino AmadoriUgo De GiorgiAndrea Rocca Androgen receptor signaling pathways as a target for breast cancer treatment. Endocrine-Related Cancer 2016, 23, R485-R498, 10.1530/erc-16-0190.
  80. Debora Basile; Marika Cinausero; Donatella Iacono; Giacomo Pelizzari; Marta Bonotto; Maria Grazia Vitale; Lorenzo Gerratana; Fabio Puglisi; Androgen receptor in estrogen receptor positive breast cancer: Beyond expression. Cancer Treatment Reviews 2017, 61, 15-22, 10.1016/j.ctrv.2017.09.006.
  81. Murtuza Rampurwala; Kari B Wisinski; Ruth O'Regan; Role of the androgen receptor in triple-negative breast cancer.. Clinical advances in hematology & oncology : H&O 2016, 14, 186-93.
  82. Tao Zuo; Parker Wilson; Ali Fuat Cicek; Malini Harigopal; Androgen receptor expression is a favorable prognostic factor in triple-negative breast cancers. Human Pathology 2018, 80, 239-245, 10.1016/j.humpath.2018.06.003.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
Video Production Service
Feedback